Vessel, method and apparatus for dissolution testing of an annular pharmaceutical delivery device

ABSTRACT

The invention relates to a vessel for dissolution testing of a pharmaceutical delivery device, comprising: an inert vessel wall and an inert vessel bottom such that the vessel is able to hold a fluid medium; an inert retainer provided by or at the vessel wall or vessel bottom, for holding a pharmaceutical delivery device; and which retainer allows a passageway to the vessel bottom for a sampling tube. The invention further relates to a method for preparing such a vessel; a dissolution method using such a vessel and an apparatus comprising such a vessel.

This invention relates to a vessel, method and apparatus for dissolutiontesting of a pharmaceutical delivery device, and more particular such avessel, method and apparatus for testing the dissolution of an annularpharmaceutical delivery device, which floats in a fluid medium.

Dissolution testing as such is well known in the art and is for exampledescribed in “Remington: The Science and Practice of Pharmacy”, 20thedition, edited by Alfonso R. Gennaro et al., published by Lippincott,Williams & Wilkens, in 2000. Dissolution testing is commonly carried outduring pharmaceutical formulation development, stability determination,analytical development, quality control, to establish batch-to-batchconsistency or as a means by which to correlate in-vitro and in-vivodrug release characteristics.

U.S. Pat. No. 5,412,979 relates to a vessel, method and apparatus fordissolution testing of a swellable dosage form, which floats in a fluidmedium. The vessel comprises a disk, adapted to engage the vessel wallat a location approximately 40 millimetres from the lowermost portion ofthe bottom of the vessel. The disk has an annular ring assembly, whichcircumferentially encloses a screen mesh. The swellable dosage form isretained in the space below the screen mesh and the vessel bottom.

WO-A-9628717 also relates to a dissolution testing vessel comprising aninserted mesh or grille to prevent a formulation undergoing dissolutiontesting from floating freely at the surface of the testing medium. Inone embodiment the inserted mesh or grille rests on one or moreprojections which project inwardly from the interior wall of the vessel.

The presence of the mesh screen is disadvantageous when samples are tobe taken. Furthermore, dissolution testing of pharmaceutical deliverydevices can require sink conditions, in which case the mesh screen isalso disadvantageous. To obtain such sink conditions the dissolutionvessel is to be regularly emptied and refilled with fresh dissolutionmedium during the testing period. When samples are taken manually and/orthe dissolution vessel is emptied manually, the mesh screen can beremoved manually before sampling and/or emptying. Such an act is,however, troublesome. Furthermore care should be taken to place the meshscreen back in the correct position. When samples are takenautomatically and/or the dissolution vessel is emptied automatically,samples cannot be taken in the lower part of the dissolution vessel andthe lower part of the dissolution vessel cannot be emptied. Anadditional disadvantage is that the screen mesh is held loosely in thevessel, and can change position during dissolution testing. The vesselcomprising the mesh screen is further disadvantageous for dissolutiontesting of relatively large dosage forms, which can be pressed againstthe mesh screen and be damaged.

Therefore, an improved vessel, method and apparatus for dissolutiontesting of a pharmaceutical delivery device is desirable.

The present invention provides a vessel for dissolution testing of apharmaceutical delivery device, comprising:

an inert vessel wall and an inert vessel bottom such that the vessel isable to hold a fluid medium;

an inert retainer provided by or at the vessel wall or vessel bottom,for holding a pharmaceutical delivery device; and which retainer allowsa passageway to the vessel bottom for a sampling tube.

The present invention further provides a method for preparing such avessel comprising melting or gluing the retainer to the vessel wall orvessel bottom or by applying one or more indentations to the vessel wallor vessel bottom.

The present invention further provides a method for dissolution testingof a pharmaceutical delivery device, which delivery device contains apharmaceutically and/or contraceptive effective amount of drug,comprising:

placing a fluid medium and stirring means in a dissolution vesselaccording to the invention;

placing a pharmaceutical delivery device in the retainer of thedissolution vessel according to the invention;

rotating the stirring means to circulate the fluid medium in thedissolution vessel;

sampling one or more predetermined volumes of the fluid medium atselected time intervals by means of a sampling tube.

The present invention further provides an apparatus for dissolutiontesting of a pharmaceutical delivery device, comprising:

one or more dissolution vessels according to the invention whichdissolution vessels are suitable for holding a fluid medium;

one or more stirring means;

a sampling and/or discharging device with one or more sampling and/ordischarging tubes suitable for sampling and/or discharging one or morepredetermined volume fractions of the fluid medium from the dissolutionvessels; and

optionally, a refilling device suitable for adding fluid medium to thedissolution vessels.

The following drawings have been enclosed to illustrate the presentinvention. Elements, which are substantially identical, and elements,which perform substantially the same function, are denoted in thefigures by the same numerals.

FIG. 1A is a cross-sectional side-view of a first embodiment of adissolution vessel according to the invention.

FIG. 1B is a cross-sectional top-view of the vessel according to FIG.1A.

FIG. 2A is a cross-sectional side-view of a second embodiment of adissolution vessel according to the invention.

FIG. 2B is a cross-sectional top-view of the vessel according to FIG.2A.

FIG. 3A is a cross-sectional side-view of a third embodiment of adissolution vessel according to the invention.

FIG. 3B to 3D respectively show cross-sectional top-views of the vesselaccording to FIG. 3A.

Referring to FIG. 1A, the vessel for dissolution testing (1) comprises avessel wall (2) and a vessel bottom (3) such that the vessel is able tohold a fluid medium (4). The vessel wall (2) and the vessel bottom (3)are made from an inert material. By an inert material is understood amaterial which essentially does not sorb, react or interfere in or withthe pharmaceutical delivery device being tested. In a further embodimentthe material from which the vessel wall (2) and/or the vessel bottom (3)are prepared is a transparent material. The vessel wall (2) and thevessel bottom (3) can be made from different types of inert material orfrom the same type of inert material. In an even further embodiment boththe vessel wall (2) and the vessel bottom (3) are made from the sametype of inert material. In an even further embodiment the vessel wall(2) and the vessel bottom (3) form one entity, wherein the vessel wall(2) gradually changes into the vessel bottom (3). Examples of suitablematerials include glass or an inert plastic. In another embodiment thematerial is glass. In a further embodiment the vessel wall (2) andvessel bottom (3) form one transparent glass entity.

In another embodiment the dissolution vessel (1) is cylindrically shapedwith a hemispherical bottom. Here, the vessel wall (2) is understood tobe the cylindrically shaped part of the vessel and the vessel bottom (3)is understood to be the hemispherical shaped part of the vessel. Theheight and inside diameter of the dissolution vessel (1) can be variedwidely and can be adapted such that the desired volume of fluid medium(4) can be held. For example, the United States Pharmacopeia describes aheight in the range from 160 to 210 mm and an inside diameter from 98 to106 mm for a dissolution vessel holding 1 L of liquid medium. In oneembodiment the height of the dissolution vessel (1) lies in the range of5 to 30 cm, in a further embodiment it lies in the range of 10 to 25 cm,and in an even further embodiment it lies in the range of 10 to 20 cm.In another embodiment the inside diameter of the dissolution vessel liesin the range of 2 to 15 cm, in a further embodiment it lies in the rangeof 3 to 11 cm, and in an even further embodiment it lies in the range of5 to 8 cm.

The vessel (1) is able to hold a fluid medium (4). The fluid medium (4)can be any medium suitable for dissolution testing, including forexample, organic solvents such as alkanols and esters; water; acidicsolutions, such as for example aqueous solutions of hydrochloric acid;and phosphate buffers. The fluid medium (4) can be selected based uponthe nature and target site of the pharmaceutical delivery device (8).For example, a fluid medium (4) can be used which is to simulate gastricfluid or intestinal fluid. In a further embodiment the fluid medium (4)is selected from the group consisting of water; dilute aqueous solutionsof hydrochloric acid, such as for example HCl solutions in the rangefrom 0.001 to 0.5N HCl, and in yet another embodiment in the range from0.01 to 0.1N HCl; and phosphate buffers. In an even further embodimentthe fluid medium is water. The pH of the fluid medium (4) can varywidely. In one embodiment the pH lies in the range from 1 to 12, and ina further embodiment the pH lies in the range from 1 to 8. In anotherembodiment the pH of the fluid medium (4) simulates the pH of thetargeted place of dissolution in the human body. For example, to mimicthe environment of the stomach, a fluid medium (4) with a pH of about 1can be used; and to mimic the pH of the lumen of the intestine a pH ofabout 6.6 can be used.

Provided by or at the vessel wall (2) or vessel bottom (3) there is aretainer (see 5 in FIG. 1A; 6 in FIG. 2A; and 7 in FIG. 3A), whichretainer (5; 6; 7) is intended for holding a pharmaceutical deliverydevice (See 8 in FIG. 1A) and which retainer allows a passageway to thevessel bottom (3) for a sampling tube. The dimensions of the retainerare such that a pharmaceutical delivery device can be held submerged inthe dissolution medium in a suitable manner.

The retainer (5; 6; 7) is prepared from an inert material. The retainer(5; 6; 7) can be prepared from the same material as the vessel wall (2)or vessel bottom (3) or from a different material. Suitable materialsinclude stainless steel, an inert plastic or glass. In a furtherembodiment the retainer is prepared from glass. In one embodiment theretainer (5; 6; 7) is located at a distance of ⅛ to ½ of the height ofthe dissolution vessel (1) from the vessel bottom (3). In anotherembodiment this distance lies in the range from 0.5 to 10 cm, and in afurther embodiment this distance lies in the range of 1 to 6 cm.

In one embodiment the retainer comprises an annular plate (see 5 in FIG.1A and 1B), which annular plate comprises a passageway (9) for asampling tube in the middle, and which annular plate (5) is placedinside the dissolution vessel (1) at the vessel wall (2). The annularplate (5) can be made of any inert material, but in a further embodimentit is made of inert plastic, glass, stainless steel, or a combinationthereof. In an even further embodiment the annular plate is manufacturedfrom glass. The annular plate (5) can comprise a number of holes (10) toprovide a better contact of the fluid medium (4) above the annular plate(5) and the fluid medium (4) below the annular plate (5).

The width of the annular plate is not critical and can be chosen suchthat a desired pharmaceutical delivery device (8) can be held. In oneembodiment the width lies in the range of 0.2 to 6 cm, in a furtherembodiment the width lies in the range from 0.5 to 3 cm, and in an evenfurther embodiment it lies in the range from 0.5 to 2 cm. The passageway(9) in the middle of the annular plate (5) has a diameter, whichdiameter allows a smooth passage for a sampling tube. In a furtherembodiment the diameter of the passageway (9) is therefore at least 1cm, and in an even further embodiment at least 2 cm; in yet an evenfurther embodiment it is at least 3 cm. In another embodiment, diametersup to 20 cm are used; in another embodiment diameters up to 10 cm areused, and in yet another embodiment diameters up to 6 cm are used. Useof the separate annular plate (5) as described, however, has thedisadvantage that the retainer is fitted loosely in the dissolutionvessel (1), and can change position during dissolution testing.

In a further embodiment therefore, the retainer is provided by thevessel wall (2) or vessel bottom (3) itself, that is, it is permanentlyfixed to the vessel wall (2) or vessel bottom (3). In a furtherembodiment such a retainer is provided by the vessel wall (2), where thevessel wall is understood to be that part of the vessel which forms the(essentially vertical) sides of the vessel. Such a retainer (see 6 inFIG. 2A; and 7 in FIG. 3A) can have any form suitable for holding apharmaceutical delivery device (8) and allowing a passageway (9) to thevessel bottom (3) for a sampling tube. Suitable ranges for the diameterof the passageway (9) include those that are described above. In oneembodiment the retainer comprises one or more annular ledges or rims(see 6 in FIG. 2A and 2B); one or more bulges (see 7 in FIG. 3A, FIG. 3Band FIG. 3C); one or more hooks (not shown) or a combination thereof.The annular ledges or rims (6), bulges (7) or hooks are protrudinginwardly from the vessel wall (2) or vessel bottom (3). The bulges (7)and hooks have the further advantage that the contact between theretainer and the tested pharmaceutical delivery device is kept to aminimum.

In a further embodiment the retainer consists of two elements providedby the vessel wall (2) or vessel bottom (3), one upper element and onelower element. In an even further embodiment both these elements areprotruding inwardly from the vessel wall (2) or vessel bottom (3). Inone embodiment the retainer comprises two annular ledges or rims (see 6a and 6 b in FIG. 2A) or two sets of bulges (see 7 a and 7 b in FIG.3A); one upper annular ledge or rim (6 a) or upper set of bulges (7 a),and one lower annular ledge or rim (6 b) or lower set of bulges (7 b).

In a further embodiment each set of bulges or hooks comprises from 2 to50 bulges or hooks, in a yet further embodiment each set comprises from2 to 10 bulges or hooks and in a still further embodiment from 3 to 5bulges or hooks. In another embodiment the bulges (7) within one set arelocated equidistantially from each other.

Furthermore in yet another embodiment, an upper set of bulges (see 7 ain FIG. 3A and FIG. 3B), is located in a staggered position with regardto a lower set of bulges (see 7 b in FIG. 3A and FIG. 3D). In a furtherembodiment the distance between an upper annular ledge or rim (6 a) anda lower annular ledge or rim (6 b); or between an upper set of bulges (7a) and a lower set of bulges (7 b), is such that a pharmaceuticaldelivery device (8) can be loosely held in between. In one embodiment,this distance lies in the range from 0.5 to 4 cm, and in a furtherembodiment this distance lies in the range from 1 to 3 cm.

As described above the pharmaceutical delivery device (8) can be locatedbetween two annular ledges or rims (see 6 in FIG. 2A); between two setsof bulges (see 7 in FIG. 3A); or within one set of hooks. The width ofthe annular ledge or rim can be chosen such that a desiredpharmaceutical delivery device (8) can be held. In one embodiment thewidth of such an annular ledge or rim (6) lies in the range of 0.05 to 3cm, in a further embodiment the width lies in the range of 0.1 to 2 cm,and in an even further embodiment in the range from 0.2 to 1.5 cm.Similarly the height of the bulges (7) or hooks in the directionprotruding inwardly perpendicular to the vessel wall (2) or vesselbottom (3) can be chosen such that a desired pharmaceutical deliverydevice (8) can be held. In one embodiment the height lies in the rangeof 0.05 to 3 cm, in a further embodiment the height lies in the range of0.1 to 1.5 cm, and in an even further embodiment in the range from 0.2to 1.0 cm.

The retainer (6; 7) can be permanently fixed to the vessel wall (2) orvessel bottom (3) by, for example, gluing or melting, after thedissolution vessel (1) itself has already been manufactured.Alternatively, the retainer (6; 7) can be permanently fixed to thevessel wall (2) or vessel bottom (3) during manufacture of thedissolution vessel itself. In this embodiment the material of theretainer can be the same or a different material from the material ofthe vessel wall (2) or vessel bottom (3). In another embodiment theretainer and vessel wall (2) or vessel bottom (3) are manufactured fromthe same material, which material is in yet another embodiment glass oran inert plastic and in even a further embodiment the material is glass.

In a further embodiment, the retainer is part of the vessel wall (2) orvessel bottom (3) and is provided by one or more indentations of thevessel wall or vessel bottom. Such an indentation can be circular,resulting in an annular ledge or rim (6); or pointed, resulting in abulge (7). The indentation or indentations can be applied during themanufacture of the dissolution vessel (1) or afterwards.

This invention therefore also provides a method for preparing thedissolution vessel according to the invention by melting or gluing aretainer to a vessel wall or vessel bottom as described above or byapplying one or more indentations in a vessel wall or vessel bottom asdescribed above.

In a further embodiment, the indentation is applied by warming thematerial of the vessel wall (2) or vessel bottom (3) to an elevatedtemperature where the material becomes soft; and subsequently pressingthe material inwardly to a sufficient extent. In yet a furtherembodiment, the retainer comprises two sets of 3 bulges (see 7 a and 7 bin FIG. 3A), viz. one upper set and one lower set in a staggeredposition, formed by indentation of the vessel wall (2) or vessel bottom(3).

The vessel according to the invention is suitable for testing thedissolution of a wide range of pharmaceutical delivery devices (8). Thevessel according to the invention is, however, especially suitable fortesting the dissolution of a pharmaceutical delivery device (8) havingan annular shape (i.e. a ring-shaped device). The outside diameter andthe thickness of the annular pharmaceutical delivery device can varywidely. In one embodiment, the outside diameter lies in the range from 3to 10 cm, and in a further embodiment the outside diameter lies in therange of 4 to 8 cm; and in another embodiment the thickness lies in therange from 0.1 cm to 1 cm and in a further embodiment the thickness liesin the range from 0.2 cm to 0.7 cm. In a further embodiment the annularpharmaceutical delivery device (8) is made of a flexible material, suchthat it can easily be placed inside the retainer (5; 6; 7). In oneembodiment, when testing the dissolution of such an annularpharmaceutical device, a vessel according to the invention is usedhaving an inner diameter slightly larger than the outer diameter of theannular pharmaceutical device, wherein the ratio from the inner diameterof the dissolution vessel according to the invention to the outerdiameter of the annular pharmaceutical delivery device lies in the rangefrom 1.0001:1 to 1.5:1, and in a further embodiment lies in the rangefrom 1.005:1 to 1.1:1.

The dissolution vessel according to the invention is further especiallysuitable for dissolution testing of annular pharmaceutical deliverydevices, which float in the fluid medium. Such a tendency to floatcould, for example, be due to the inactive ingredients used. In oneembodiment the annular pharmaceutical delivery device is a flexibleannular pharmaceutical delivery device comprising at least onecompartment which comprises a thermoplastic polymer core and athermoplastic polymer skin covering the core, which core comprises amixture of a progestogenic compound and an estrogenic compound, andwhich skin is permeable for the progestogenic and estrogenic compounds.

Examples of annular pharmaceutical delivery devices for which thedissolution vessel according to the invention is especially suitableinclude the annular pharmaceutical delivery devices described in forexample U.S. Pat. No. 5,989,581, WO-A-97/02015, U.S. Pat. No. 4,237,885,EP-A-0876815, EP-A-0050867, US-A-4292965, U.S. Pat. No. 4,596,576, whichare hereby incorporated by reference.

In addition to the above, one or more stirring means (11) can bepresent. Such stirring means (11) can be any means known in the art forstirring the fluid medium in the dissolution vessel and include forexample paddles and magnetic stirrers. In one specific embodiment amagnetic stirrer is used.

This invention further provides a method for dissolution testing ofpharmaceutical delivery device, which delivery device contains apharmaceutical and/or contraceptive effective amount of drug,comprising:

placing a fluid medium and stirring means in a dissolution vesselaccording to this invention;

placing a pharmaceutical delivery device in the retainer of thedissolution vessel according to this invention;

rotating the stirring means to circulate the fluid medium in thedissolution vessel;

sampling one or more predetermined volumes of the fluid medium atselected time intervals by means of a sampling tube.

The pharmaceutical delivery device can be any delivery device known inthe art, but in a specific embodiment it is an annular delivery deviceas described above. In a further embodiment the pharmaceutical deliverydevice is an annular delivery device as described in U.S. Pat. No.5,989,581.

The fluid medium can be any fluid medium suitable for dissolutiontesting. In a further embodiment, however, it is a fluid medium asdescribed above. In a further embodiment water is used as a fluidmedium. The amount of fluid medium used can be chosen such to enable thedissolution measurement of the specific drug concentration in thepharmaceutical delivery device. In one embodiment the volume lies in therange of 25 to 1000 ml, in a further embodiment the volume lies in therange from 50 to 500 ml. In yet a further embodiment, volumes of 100 mlor 200 ml are used. The temperature of the fluid medium can vary widely,but in a further embodiment the temperature is similar to thetemperature of the human body and lies in the range from 36° C. to 38°C., and in an even further embodiment the temperature lies in the rangefrom 36.5° C. to 37.5° C. The temperature of the fluid medium can bemaintained by any manner known in the art, including, for example bymeans of a water bath or by means of heating jacket.

Suitable stirring means are as described above.

The fluid medium is sampled by means of a sampling tube. The samplingtimes can be chosen such that a sufficient amount of samples is takenduring the release time of drug from the pharmaceutical delivery device.The exact time intervals will depend on the release time of the drugfrom the pharmaceutical delivery device. For example, if an immediaterelease delivery device is tested, time intervals can, for example, liein a range from 1 minute to 1 hour. If a slow-release delivery device istested, such time intervals can, for example, lie in the range from 0.5hour to 48 hours. Depending on the goal of the dissolution test thesampling can take place only once or more often. In one embodiment thefluid medium is sampled only once, and it is sampled after in the rangefrom 50 to 100% of the drug has been released. In a further embodimentthe fluid medium is sampled in the range from 1 to 30 times during therelease time of drug from the pharmaceutical delivery device, in an evenfurther embodiment the fluid medium is sampled in the range from 3 to 20times and in an even further embodiment the fluid medium is sampled inthe range from 4 to 15 times.

If it is necessary to obtain sink conditions, in a further embodimentthe steps of discharging the total of fluid medium from the dissolutionvessel and refilling the dissolution vessel with fresh fluid mediumafter sampling, are added. The fluid medium can be discharged from thedissolution vessel by means of a discharging tube. Similarly, thedissolution vessel can be refilled with fresh fluid medium via arefilling tube. In another embodiment the sampling tube as describedabove is used as discharging tube and/or refilling tube, when necessary.

The samples taken are to be analysed to establish the drug concentrationat the sampling moment. The samples can be analysed after all sampleshave been taken, but in another embodiment they are analysed directlyafter sampling. The samples can be analysed by using any method known inthe art to be suitable therefore. Examples of possible analysetechniques include fluorescence, indirect or direct ultraviolet (UV),Infrared (IR), refractometry, scattering techniques, near-Infrared(NIR), electrochemical and/or Raman spectroscopy techniques.

Furthermore this invention provides an apparatus for dissolution testingof a pharmaceutical delivery device, comprising:

one or more dissolution vessels according to the invention, whichdissolution vessels are suitable for holding a fluid medium;

one or more stirring means;

a sampling and/or discharging device with one or more sampling and/ordischarging tubes suitable for sampling and/or discharging one or morepredetermined volume fractions of the fluid medium from the dissolutionvessels; and

optionally, a refilling device suitable for adding fluid medium to thedissolution vessels.

The sampling and/or discharging device can be used to take onepredetermined volume fraction of the fluid medium for sampling purposesor to take a series of predetermined volume fractions to discharge thetotal of fluid medium from the dissolution vessel. In a furtherembodiment the discharging device and the refilling device are one andthe same device, which device can be operated in two oppositedirections, viz. to transfer fluid medium from the dissolution vesselsto a predetermined discharging position and to transfer fluid mediumfrom a predetermined storing position to the dissolution vessels.

The apparatus according to the invention can be used in a set-upcomprising in addition an analytical device. The analytical device canbe a device for measuring the drug concentration in a sample of thefluid medium by fluorescence, ultraviolet (UV), Infrared (IR),near-Infrared (NIR), electrochemical and/or Raman spectroscopytechniques.

The apparatus can be operated manually or automatically. In anotherembodiment of the invention, however, the apparatus is operatedautomatically, wherein a motor, directed by a computing device, operatesthe stirring means, the sampling and/or discharging device and/orrefilling device. In a further embodiment any samples are furthertransferred automatically to an analytical device, where they areautomatically analysed. In an even further embodiment the analyticaldata is subsequently gathered automatically by the computing device andin yet an even further embodiment the data is automatically visualisedby this same computing device.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention that will be readily apparent tothose skilled in the art are contemplated to be encompassed within theappended claims.

1-11. (canceled)
 12. A vessel for dissolution testing of an annularpharmaceutical delivery device, comprising: an inert vessel wall and aninert vessel bottom such that the vessel is able to hold a fluid medium;and an inert retainer provided by or at the vessel wall or vesselbottom, for holding the annular pharmaceutical delivery device andproviding a passageway to the vessel bottom for a sampling tube.
 13. Thevessel according to claim 12, wherein the vessel wall and the vesselbottom together form one transparent glass entity.
 14. The vesselaccording to claim 12, wherein the retainer comprises an annular plate,which annular plate comprises the passageway for the sampling tube inthe middle of the annular plate, and the annular plate is placed insidethe vessel at the vessel wall.
 15. The vessel according to claim 12,wherein the retainer is permanently fixed to the vessel wall or thevessel bottom.
 16. The vessel according to claim 12, wherein theretainer is selected from the group consisting of one or more annularledges protruding inwardly from the vessel wall or vessel bottom, one ormore annular rims protruding inwardly from the vessel wall or vesselbottom, and one or more bulges protruding inwardly from the vessel wallor vessel bottom.
 17. The vessel according to claim 16, wherein theretainer comprises two sets of bulges formed by indentation of thevessel wall or vessel bottom.
 18. A method for preparing a vesselaccording to claim 15, comprising melting or gluing the retainer to thevessel wall or vessel bottom.
 19. A method for dissolution testing of anannular pharmaceutical delivery device containing an amount of a drug,the method comprising: placing a fluid medium and stirring means in adissolution vessel comprising: an inert vessel wall and an inert vesselbottom such that the vessel is able to hold the fluid medium, and aninert retainer provided by or at the vessel wall or vessel bottom, forholding the annular pharmaceutical delivery device and providing apassageway to the vessel bottom for a sampling tube; placing the annularpharmaceutical delivery device in the retainer; rotating the stirringmeans to circulate the fluid medium in the dissolution vessel; insertinga sampling tube through the passageway; and sampling one or morepredetermined volumes of the fluid medium at selected time intervals bymeans of the sampling tube.
 20. An apparatus for dissolution testing ofan annular pharmaceutical delivery device, comprising: one or moredissolution vessels according to claim 1, one or more stirring means;and a sampling and/or discharging device with one or more samplingand/or discharging tubes suitable for sampling and/or discharging one ormore predetermined volume fractions of the fluid medium from thedissolution vessels.
 21. The apparatus of claim 20, further comprising arefilling device suitable for adding fluid medium to the dissolutionvessels.